This SCOR application seeks to establish a center for the study of the molecular mechanisms controlling lung morphogenesis during the embryonic and perinatal period of development. The proposal is based on the hypothesis that interactions- autocrine/paracrine and cell/cell - between epithelial and mesenchymal cells of the developing respiratory tract determine lung morphogenesis, alveolarization and postnatal lung function. The projects will test the hypothesis the events involved in lung morphogenesis are recapitulated, at least in part, during the repair processes following perinatal and postnatal lung injury. Elucidation of the signalling and transcriptional controls that mediate normal lung morphogenesis will provide critical insights into the process o lung injury and repair that causes acute and chronic lung diseases including bronchopulmonary dysplasia, pulmonary fibrosis, alveolar proteinosis, ARDS/RDS. The program consists of five interrelated projects and supporting Cores. I Transcriptional control of respiratory epithelial differentiation - TTF-1 and HNF family members. Jeffrey Whitsett, PI II Role of TGF-alpha and TGF-beta in pulmonary morphogenesis and oxygen injury. Thomas Korfhagen, PI III FGF-Vll (KGF) and receptors in lung morphogenesis and repair. James Greenberg, PI IV GM-CSF and its receptors in Type II cell proliferation differentiation and function. Ward Rice, PI V Smooth muscle cell differentiation and gene regulation during lung morphogenesis. James Lessard, PI Core components will provide technical and intellectual support for the individual projects and include: A) Physiology, B) Molecular Morphology, C) Cell Culture, D) Transgenic/Animal, and B) Clinical Cores. The SCOR investigators will make extensive use of transgenic and bitransgenic mouse models generated by homologous recombination and/or gene addition to alter the expression of transcription factors and/or signalling molecules and their receptors in specific subsets of pulmonary cells. Preliminary data in each of the SCOR projects provides strong inference that the molecular systems chosen for study are likely to play critical roles in lung growth, differentiation, morphogenesis, pulmonary fibrosis and/or repair. Elucidation of the signalling pathways that mediate normal and abnormal responses to lung injury will likely provide novel insights into the pathogenesis of neonatal lung disease and provide a foundation for the development of new therapies for the prevention or amelioration of pulmonary diseases in infants.